SAN FRANCISCO -- Oral semaglutide had a cardiovascular safety profile similar to that seen previously with the injectable form (Ozempic) in patients with type 2 diabetes, according to a pre-approval study presented here.

In more than 3,000 older patients with high risk for cardiovascular disease, 3.8% of individuals on oral semaglutide and 4.8% in a placebo group experienced death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (hazard ratio 0.79, 95% CI 0.57-1.11, P<0.0001 for noninferiority), reported Mansoor Husain, MD, of Toronto General Hospital, and colleagues in The New England Journal of Medicine.

Patients given oral semaglutide also had about a 50% reduction in cardiovascular death (15 vs 30; HR 0.49, 95% CI 0.27-0.92) and all-cause mortality (23 vs 45; HR 0.51, 95% CI 0.31-0.84) compared to the placebo group, although few of these events occurred across the trial, Husain said.

"Compared to commonly used alternatives, oral semaglutide has similar safety and tolerability as other drugs in its class," Husain said at the press conference. "The PIONEER 6 safety study showed oral semaglutide is safe in patients with type 2 diabetes at high cardiovascular risk, with a non-significant 21% reduction in three-component major adverse cardiac events over a median follow up of just under 16 months."

The PIONEER Trials

Injectable semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to lower glucose, promote weight loss, and improve cardiovascular risk in patients with preexisting conditions. Some patients had needles, however, and they may therefore prefer a pill form.

No other GLP-1 agonist is yet available in oral form.

In the previously reported PIONEER 3 trial, oral semaglutide significantly decreased hemoglobin A1c and promoted weight loss in patients with type 2 diabetes compared to sitagliptin (Januvia). That study tested three doses of oral semaglutide: 3, 7, and 14 mg/day. The 3-mg/day dose failed to outperform sitagliptin, while the 14-mg/day dose led to high rates of discontinuation because of adverse gastrointestinal effects.

The open-label PIONEER 7 trial also presented at this year's meeting aimed to steer patients towards an individualized treatment dose, using a flexible regimen that started them on 3 mg/day uptitrated at 8-week intervals to 7 or 14 mg/day to optimize response against side effects.

Under this regime, oral semaglutide was superior to sitagliptin (100 mg) in improving glycemic control and weight loss at 52 weeks, with similar rates of adverse events and drug discontinuation observed in PIONEER 3.

For this study, researchers recruited individuals age 50 or over with evidence of cardiovascular or chronic kidney disease (85%) and patients at least age 60 with subclinical evidence of cardiovascular disease (15%). Excluded were patients with recent cardiovascular events like myocardial infarction or stroke; those taking GLP-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, or pramlintide; or those with hemodialysis, peritoneal dialysis, severe renal impairment, or proliferative retinopathy.

Patients were assigned to receive either 14 mg semaglutide or placebo in addition to standard-of-care treatment. The trial was event-driven and patients were followed-up every 6-7 weeks via in-person visits or telephone calls, and then 5 weeks after one of the primary cardiovascular outcomes occurred; median time patients stayed enrolled was 15.9 months and 99.7% of patients completed the study.

The trial, designed to preclude an 80% excess in cardiovascular risk, was not able to determine superiority due to the low number of events that occurred (137) and the relatively short duration of the trial, the authors reported.

In total, 3,183 patients, mean age of 66, were included. Two-thirds were men. Across groups, patients did not significantly differ, with both treatment arms having mean HbA1c of 8.2%, body mass index of 32, and estimated glomerular filtration rate of 74 mL/min/1.73 m2.

Patients had diabetes a mean 15 years before enrollment and blood pressure and cholesterol levels were well-controlled in both groups, Husain reported. Most were on metformin (77%), insulin (61%), or antihypertensive medication (85%).

Overall, 23 patients in the semaglutide group and 45 on placebo died in the trial, most commonly due to cardiovascular complications. Also, severe hypoglycemia was more common in the intervention arm than in the placebo group (1.4% vs 0.8%), though all cases occurred with concomitant insulin or sulfonylureas, the authors noted.

Other Findings

Oral semaglutide did improve glycated hemoglobin levels versus placebo, though the authors noted that PIONEER 6 was not designed to evaluate its efficacy.

As in the other trials, the most common side effects in PIONEER 6 were gastrointestinal (6.8% with semaglutide vs 1.6% with placebo); rates of serious adverse events, however, were similar between semaglutide and placebo (2.6% vs 3.0%, respectively). The most common adverse event was nausea (2.9% with semaglutide vs 0.5% with placebo), said co-investigator John Buse, MD, PhD, of the University of North Carolina, who also discussed the findings.

This could be one advantage of the injectable formulation, since it can be titrated very slowly to essentially eliminate nausea as a side effect, whereas the oral formulation cannot, Buse said.

"Most people who can tolerate the 3 mg dose can tolerate the 7 mg and the 14 mg, so the flexible dose adjustment was a bit of a failure in that we weren't able to show that more people can tolerate it and go on to full therapy," Buse told MedPage Today.

Because most side-effects occurred in the first 8 weeks, clinicians might consider starting at an even lower dose than 3 mg a day, wrote Michael Nauck, MD, and Juris Meier, MD, both of Ruhr-University Bochum in Germany, in an editorial published in The Lancet Diabetes and Endocrinology. Pairing GLP-1 receptor agonists with fixed-ratio combinations of insulin (like insulin degludec plus liraglutide) may also lower GI events, they added.

Meanwhile, other recently released trials within the PIONEER study group continue to build the resume for GLP-1 receptor agonists. Also published to coincide with this year's meeting, PIONEER 4 showed oral semaglutide was non-inferior to subcutaneous liraglutide (Victoza) in reducing HbA1c and superior in inducing weight loss.

"Considering the high variability between patients in susceptibility to weight loss (and side-effects), the hints of genetic determination of such variability, and the need for better glycaemic control and more extensive decreases in body weight in many patients, the one-size-fits-all approach that has been used traditionally in the GLP-1 receptor agonist field could now be challenged and higher doses be explored for the potential benefit of those who tolerate them," the editorialists wrote.

"By eliminating the barrier of injection, oral semaglutide has potential for wide usage in the treatment of type 2 diabetes, including in high-risk patients with cardiovascular disease and chronic kidney disease," Husain concluded.

Husain served on the advisory panel or as a consultant for AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., and Novo Nordisk.

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